present invention concerns the use of caffeic acid phenethyl esters as radiation sensitizers in the treatment of tumors in subjects in need thereof.
Adenocarcinoma of the prostate is the most commonly diagnosed non-skin cancer and the second leading cause of cancer deaths in the United States (F. Keely and L. Gomella, Epidemiology of Prostate Cancer, in Prostate Cancer, M. Ernstoff, J. Heany, and R. Peschel, Eds., 1998, p.2-14). Currently, the only therapies that have shown significant promise for curability of localized disease are radical prostatectomy and radiation therapy (RT). Selection of each type of treatment depends mainly upon tumor stage, with the majority of patients with A2 and B1 tumors receiving surgery, while those with stages B2, or C and higher-grade tumors are treated with radiation (R. Peschel, External Beam Radiation Therapy for Local Prostate Cancer, in Prostate Cancer, p. 117-136).
Studies have suggested that adjuvant radiotherapy following prostatectomy provides superior results in terms of biochemical relapse (Prostate Specific Antigen levels) than surgery alone (R. Peschel, supra). Radiation therapy can consist of Conventional External Beam Radiotherapy, Three-Dimensional Conformal Radiation Therapy, or Radioactive Implant therapy. The latter modality, which was first developed in the early 1970""s and is currently experiencing a resurgence, offers the advantage of delivery of relatively high-dose radiation therapy in a localized area. Despite the effectiveness of these different RT modalities in achieving local control of the disease and reducing the mortality rate of prostate cancer patients, approximately 20-40% of patients with local disease receiving irradiation will relapse at the site of irradiation (P. Scardino and T. Wheeler, NCI Monogr, 7, 95-103 (1988); J. Crook et al., Urology 45, 624-31 (1995); J. Crook et al., Cancer 79, 81-9 (1997)).
Moreover, studies have shown that cells that survive initial irradiation treatments are the ones most likely to form clones that will eventually repopulate the irradiated area and potentially metastasize (Z. Fuks et al., Int. J. Radiat. Oncol. Biol. Phys. 21, 537-547 (1991)). Thus, new combined modalities using agents that increase the lethal effects of ionizing radiation have the potential of reducing the probability of tumor recurrence and to increase disease-free survival times in patients treated with RT. Though a number of such agents have been shown to be effective in sensitizing prostate tumor cells to Ionizing Radiation (IR) in vitro, these results have not yet translated into effective combined modalities in the clinic, either because of lack of effectiveness in vivo, or because of potential toxicity or unknown long-term effects of such agents (M. Garzotto et al., Cancer Res. 59, 5194-201 (1999); K. Kimura et al., Cancer Res. 59, 1606-14 (1999)). Accordingly, there is a need for new ways to potentiate the activity of ionizing radiation in therapies for the treatment of cancers such as prostate cancer.
A first aspect of the present invention is a method of potentiating radiation therapy in a subject in need thereof, comprising administering caffeic acid phenethyl ester (CAPE) or an analog thereof (a potentiating agent or active compound) to said subject in an amount effective to potentiate radiation therapy in said subject. By xe2x80x9cpotentiating radiation therapyxe2x80x9d is meant increasing or enhancing (e.g., synergistically enhancing) the activity of radiation therapy on a tumor in said subject.
A second aspect of the present invention is a method of treating a tumor in said subject, comprising concurrently administering a potentiating agent as described above (i.e., CAPE or an analog thereof) to said subject while also administering radiation therapy (e.g., ionizing radiation) to said tumor, the potentiating agent being administered to said subject in an amount effective to potentiate the activity or efficacy of the radiation therapy (e.g., by increasing or enhancing, particularly synergistically enhancing) the activity of the radiation therapy on said subject).
A third aspect of the present invention is a method of potentiating antineoplastic therapy in a subject in need thereof, comprising administering caffeic acid phenethyl ester (CAPE) or an analog thereof (a potentiating agent) to said subject in an amount effective to potentiate antineoplastic therapy in said subject. By xe2x80x9cpotentiating antineoplastic therapyxe2x80x9d is meant increasing or enhancing (e.g., synergistically enhancing) the activity of an antineoplastic agent administered to said subject on a tumor in said subject.
A fourth aspect of the present invention is a method of treating a tumor in said subject, comprising concurrently administering a potentiating agent as described above (i.e., CAPE or an analog thereof) to said subject while also an antineoplastic agent to said subject, the potentiating agent being administered to said subject in an amount effective to potentiate the activity or efficacy of the antineoplastic agent (e.g., by increasing or enhancing, particularly synergistically enhancing) the activity of antineoplastic agent on a tumor in said subject).
A further aspect of the present invention is a composition for treating a tumor in a subject, comprising, in combination in a pharmaceutically acceptable carrier, (i) a potentiating agent comprising CAPE or an analog thereof, and (ii) an antineoplastic agent. The potentiating agent is included in the composition in an amount effective to potentiate the activity of the antineoplastic agent.
A still further aspect of the present invention is the use of an active compound as described above for the preparation of a medicament for the treatment of a disorder as described above, or carrying out a method as described above.
The present invention is explained in greater detail in the specification set forth below and the drawings herein.